title: Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity.
abstract: We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.
authors.affiliation: Immunologia, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. daniela.pende@istge.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcenaro
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
authors.forename: Stefania
authors.initials: S
authors.lastname: Martini
authors.forename: Maria Ester
authors.initials: ME
authors.lastname: Bernardo
authors.forename: Daniela
authors.initials: D
authors.lastname: Montagna
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.forename: Céline
authors.initials: C
authors.lastname: Cognet
authors.forename: Miryam
authors.initials: M
authors.lastname: Martinetti
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D020544:Graft vs Leukemia Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology*; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008297:Male; D018579:Patient Selection; D054340:Receptors, KIR / Q000378:metabolism* / Q000502:physiology*; D013379:Substrate Specificity; D014019:Tissue Donors; D014180:Transplantation / Q000502:physiology; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: C433932:KIR2DS2 protein, human; D054340:Receptors, KIR